This project is a component of the Lung Inflammatory Disease program of the Programs of Excellence in Glycosciences (LID-PEG). In this project we seel<to develop leukocyte targeted nanoparticles bearing glycan ligands of siglecs, and investigate their use in diagnosis and therapy of lung and cardiovascular diseases. The siglecs are a family of immune receptors that bind sialic acid containing glycans as ligands. Most siglecs are expressed on leukocytes and are well documented as regulators of cell signaling in innate and adaptive immunity. Because each siglec is expressed on one or a few cell types, they are well suited as targets for cell directed therapies for diseases caused by leukocytes. The applicant's laboratory has developed nanoparticle platforms decorated with siglec ligands that are capable of selectively targeting and delivering cargo to cells expressing the corresponding siglec. In the proposed project we will use these nanoparticles to target leukocytes that play critical roles in the initiation and progression of lung and cardiovascular disease. Nanoparticles decorated with ligands to Siglec-8 (murine Siglec-F) will be used to target eosinophils, Siglec-9 (murine Siglec-E) to target neutrophils, and sialoadhesin (Sn; Siglec-1) to target monocytes/macrophages. Nanoparticles targeting each leukocyte cell type will be tested for their activity in murine models of allergic asthma and chronic obstructive pulmonary disease (COPD), and sialoadhesin (macrophage) targeted nanoparticles will be tested for diagnosis and amelioration of atherosclerotic plaque in a murine model of atherosclerosis. The results will help establish the roles of the corresponding cell types in disease processes, and document the potential utility of siglec- targeted nanoparticles in the diagnosis and treatment of lung and cardiovascular disease. RELEVANCE (See instructions): This project seeks to develop novel cell targeted nanoparticles that can deliver agents to white blood cells for diagnosis and treatment of lung and cardiovascular diseases.